TET3通过去甲基化HOTAIR调控B细胞介导肠癌免疫抑制的作用及机制研究

肠癌是我国高发恶性消化道肿瘤。聚焦肠癌免疫微环境，我们发现B细胞是肠癌中的重要免疫细胞：其可以分泌IgG抗肿瘤，亦可表达抑制性分子促肿瘤。然而，伴随肠癌进展，B细胞逐步上调抑制性分子IL-10、PD-L1等，表现为免疫抑制性增强，其中机制不明。初步研究发现，肿瘤进展期的B细胞上调去甲基化酶TET3，是促进抑制分子IL-10/PD-L1表达的重要驱动因素，潜在机制涉及肿瘤低糖缺氧微环境及其下游靶点长链非编码RNA, HOTAIR。基于此，我们拟联合小鼠肠癌模型、肠癌样本及B细胞功能模型，借助5hmc检测、甲基化测序及基因敲除等技术，明确B细胞表达TET3与其抑制性功能及患者预后的关系，TET3通过HOTAIR调控B细胞免疫抑制作用的表观模式，以及肿瘤生长造成的低氧缺糖微环境对B细胞TET3-HOTAIR信号的启动机制。基于TET3-HOTAIR表观调控轴，探究B细胞相关肠癌诊治新策略。

Colorectal cancer (CRC) is a high incidence of malignant gastrointestinal tumors in China. We focused on the immune microenvironment of colorectal cancer and found that B cells are important immune cells in colorectal cancer. The B cells can secrete IgG against tumor and also express suppressive molecules to promote tumor. However, with the progression of colorectal cancer, B cells upregulated immunosuppressive molecules such as IL-10 and PD-L1. The mechanism underlying is not clear. Our preliminary data shows that up-regulation of demethylase TET3 in B cells may be an important driving factor to promote the expression of IL-10/PD-L1. In mechanisms, long non-coding RNA HOTAIR is the potential target of TET3. Hypoglycemia and hypoxia microenvironment can induced the expression of TET3 . Based on this data, we propose to combine mouse colorectal cancer model, human colorectal cancer samples and in vitro B cell function model, using 5hmc detection, methylation sequencing and gene knockout techniques to clarify the relationship between the expression of TET3 and the immunosuppressive function of B cells in the progression of colorectal cancer, and the prognosis will be analyzed. Furthermore, the role of HOTAIR in TET3 regulating B cell immunosuppressive effect will be clarified, as well as the regulation of hypoglycemia and hypoxia microenvironment on B cell expressing TET3,. Based on TET3-HOTAIR epigenetic axis, reversing the immunosuppressive function of B cells and activate anti-tumor immunity may provide a new strategy for clinical diagnosis and treatment of colorectal cancer.